EP0894799B1 - Indolmorphinan-derivate und medikamente zur behandlung/mittel zur vorbeugung von cerebralen störungen - Google Patents

Indolmorphinan-derivate und medikamente zur behandlung/mittel zur vorbeugung von cerebralen störungen Download PDF

Info

Publication number
EP0894799B1
EP0894799B1 EP98900228A EP98900228A EP0894799B1 EP 0894799 B1 EP0894799 B1 EP 0894799B1 EP 98900228 A EP98900228 A EP 98900228A EP 98900228 A EP98900228 A EP 98900228A EP 0894799 B1 EP0894799 B1 EP 0894799B1
Authority
EP
European Patent Office
Prior art keywords
carbon number
cerebral
epoxy
dehydro
cyclopropylmethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP98900228A
Other languages
English (en)
French (fr)
Other versions
EP0894799A4 (de
EP0894799A1 (de
Inventor
Hiroshi Nagase
Yoshifumi Imamura
Junichi Hirokawa
Susumu Matsuda
Yasushi Miyauchi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Toray Industries Inc
Original Assignee
Toray Industries Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Toray Industries Inc filed Critical Toray Industries Inc
Publication of EP0894799A1 publication Critical patent/EP0894799A1/de
Publication of EP0894799A4 publication Critical patent/EP0894799A4/de
Application granted granted Critical
Publication of EP0894799B1 publication Critical patent/EP0894799B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to indolomorphinan derivatives or pharmacologically acceptable acid addition salts thereof, and an agent for curing and preventing cerebral disorders comprising the derivatives or salts thereof, and particularly to a medicine useful for ameliorating various cerebral diseases and aftereffects thereof, and preventing the recurrence thereof.
  • Cerebrovascular diseases are possibly caused by aging, hypertension, arterial sclerosis, hyperlipidemia, and the like, and are generally referred to as "cerebral stroke".
  • cerebral vascular diseases possibly include functional disorders of the brain due to head trauma.
  • Cerebral stroke is roughly classified into ischemic (infarcted) diseases and hemorrhagic diseases.
  • the former include cerebral infarction (cerebral thrombosis, cerebral embolism), and the like, and examples of the latter include cerebral hemorrhage, subarachnoid hemorrhage, and the like.
  • the blood flow is clogged due to a cerebrovascular disorder, and thus glucose and oxygen, which are energy sources of the action of the cerebral nerve cells, are insufficiently supplied, resulting in various damages of the nerve cells.
  • These diseases are fundamentally caused by death of the cerebral nerve cells of a damage area and the periphery thereof.
  • Such cerebrovascular diseases cause occurrence of various aftereffects such as cerebrovascular dementia, which are critical medical and social problems at present.
  • Medicines which have been developed as agents for curing such cerebrovascular diseases in Japan are mainly used for ameliorating aftereffects such as psychoneurosis and the like, and main medicines have the function to increase the amount of the blood flow to the brain to promote the supply of glucose and oxygen to an ischemic area.
  • these medicines are expressed by vague terms such as medicines for ameliorating the cerebral blood flow, medicines for activating cerebral metabolism, and medicines for ameliorating cerebral function.
  • almost all of these medicines are effective in ameliorating marginal symptoms such as volition disorders, affective disorders, bahavioral abnormality, and the like, while the activity to the nucleus symptoms of dementia such as memory disorders and the like is considered as doubtful.
  • anti cerebral edema agents are clinically used, particularly, in the acute stage of a cerebrovascular disease. These agents also have no direct action on the cerebral nerve cells, but are used only for symptomatic therapy. In any case, the above present medicines have substantially no effect on damages of the cerebral nerve cells in cerebrovascular diseases, and have no action to inhibit directly the death of the cerebral nerve cells.
  • cerebral neurodegenerative diseases such as Alzheimer's disease
  • approach for elucidating causes and developing a therapeutic method is actively carried out in various fields.
  • the main object of the approach is to activate, particularly, the acetylcholine nervous system
  • approach is also carried out by employing the neuroprotective action by a substance related to a nerve growth factor, a neurotrophic factor for the death of the nerve cells due to cerebral neurodegenerative diseases. Also the effect of a medicine having the cerebral neuroprotective action is expected.
  • the present invention relates to an agent for curing and preventing cerebral disorders, and an object of the present invention is to provide a medicine useful for ameliorating various cerebral diseases and aftereffects thereof, and preventing the recurrence thereof.
  • the present invention provides a medicine useful for curing and preventing cerebral stroke, traumatic cerebral disease , cerebral edema, and cerebral neurodegenerative diseases by inhibiting various ischemic, hemorrhagic or traumatic cerebral disorders and damages of the cerebral nerve cells caused by various nerve degeneration to protect the cerebral nerve cells.
  • EP-A-614898 or WO-A- 95 31463 disclose morphinan derivatives for the treatment of the above mentioned disorders.
  • the present invention relates to an agent for curing and preventing cerebral disorders comprising an indolomorphinan derivative or a pharmacologically acceptable acid addition salt thereof, which is represented by the following formula (I):
  • Preferred embodiments of the agent for curing and preventing cerebral disorders comprising an indolomorphinan derivative or a pharmacologically acceptable acid addition salt thereof represented by formula (I) of the present invention are as follows.
  • R 1 is preferably hydrogen, alkyl having a carbon number of 1 to 5, cycloalkylmethyl having a carbon number of 4 to 7, cycloalkyenylmethyl having a carbon number of 5 to 7, phenyl, naphthyl, phenylalkyl having a carbon number of 7 to 13, alkenyl having a carbon number of 2 to 7, furan-2-ylalkyl having a carbon number of 1 to 5 (wherein the carbon number indicates the number of the carbons of the alkyl moiety of furan-2-ylalkyl), or thiophene-2-ylalkyl having a carbon number of 1 to 5 (wherein the carbon number indicates the number of the carbons of the alkyl moiety of thiophene-2-ylalkyl), and more preferably hydrogen, methyl, ethyl, propyl, butyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, benzyl, phenet
  • R 2 and R 3 are preferably hydrogen, hydroxy, methoxy, ethoxy, propoxy, acetoxy, benzyloxy, or benzoyloxy. Of these groups, R 2 is more preferably hydroxy, methoxy, or acetoxy, and R 3 is more preferably hydrogen, hydroxy or methoxy.
  • R 4 is preferably (CH 2 ) 2 -R 16 , (CH 2 ) 3 -R 16 , (CH 2 ) 4 -R 16 and the like.
  • R 9 is preferably methyl, phenyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, indolyl, quinolyl, benzyl, or cinnamyl.
  • R 9 except methyl the aryl moiety may be substituted by a substituent R 15 .
  • one or the same or different two substituents are preferably selected from fluoro, chloro, bromo, nitro, amino, methyl, methoxy, isothiocyanato, trifluoromethyl, trifluoromethoxy and cyano, and, particularly, one substituent is preferably selected from fluoro, chloro, bromo, nitro, methyl, methoxy, and trifluoromethyl.
  • R 5 is preferably fluoro, chloro, bromo, amino, methyl, ethyl, propyl, butyl, heptyl, cyclopentyl, cyclohexyl, methoxy, or ethoxy, and more preferably fluoro, chloro, bromo, methyl, heptyl, cyclopentyl, cyclohexyl or methoxy.
  • R 4 is R 6
  • R 5 presents R 11 .
  • groups as R 11 include fluoro, chloro, bromo, iodo, nitro, methyl, ethyl, propyl, butyl, heptyl, methoxy, isothiocyanato, trifluoromethyl, trifluoromethoxy, cyano, phenyl, hydroxymethyl, hydroxyethyl, hydroxyprpyl, SR 12 , SOR 12 , SO 2 R 12 , CH 2 CO 2 R 12 , (CH 2 ) 2 CO 2 R 12 , (CH 2 ) 3 CO 2 R 12 , SO 2 NR 13 R 14 , CONR 13 R 14 , CH 2 NR 13 R 14 , (CH 2 ) 2 NR 13 R 14 , (CH 2 ) 3 NR 13 R 14 , CH 2 N(R 13 )COR 14 , (CH 2 ) 2 N(R 13 )COR 14 , and (CH 2 ) 3 N(R 13 )COR 14 .
  • R 12 is preferably methyl or ethyl
  • R 13 is preferably hydrogen or methyl
  • R 14 is preferably hydrogen, methyl, ethyl, propyl, butyl, cyclopropylmethyl, or cyclobutylmethyl.
  • the fused ring structure A is preferably a benzo structure unsubstituted or substituted by 1 or 2 groups R 10 , or an indeno or naphtho structure unsubstituted by R 10 .
  • a benzo structure unsubstituted or substituted by one R 10 is preferable.
  • two R 5 groups form a benzo structure as the fused ring structure A
  • examples of compounds of formula (I) include compounds represented by the following formulae (IIIa), (IIIb), (IIIc) and (IIId).
  • the compounds of formula (I) are not limited to these compounds.
  • R 10 and R 11 is preferably fluoro, chloro, bromo, iodo, nitro, methyl, ethyl, propyl, butyl, methoxy, isothiocyanato, trifluoromethyl, trifluoromethoxy, cyano, phenyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, SR 12 , SOR 12 , SO 2 R 12 , CH 2 CO 2 R 12 , (CH 2 ) 2 CO 2 R 12 , (CH 2 ) 3 CO 2 R 12 , SO 2 NR 13 R 14 , CONR 13 R 14 , CH 2 NR 13 R 14 , (CH 2 ) 2 NR 13 R 14 , (CH 2 ) 3 NR 13 R 14 , CH 2 N(R 13 )COR 14 , (CH 2 ) 2 N(R 13 )COR 14 , or (CH 2 ) 3 N(R 13 )COR 14 .
  • R 12 is preferably methyl or ethyl
  • R 13 is preferably hydrogen, methyl or ethyl
  • R 14 is preferably hydrogen, ethyl, propyl, butyl, cyclopropylmethyl, or cyclobutylmethyl.
  • R 10 and R 11 may form a bridged structure of R 10 -R 11 together.
  • an ethano or o-benzeno structure is preferable as the bridged structure.
  • the bridged structure is ethano
  • the fused ring structure A is benzo
  • examples of compounds of formula (I) include compounds represented by the following formulae (IVa), (IVb), (IVc) and (IVd). The compounds of formula (I) are not limited to these compounds.
  • Preferable examples of pharmacologically acceptable acid addition salts include inorganic salts such as a hydrochloride, a sulfate, a nitrate, a hydrobromide, a hydroiodide, a phosphate, and the like; organic carboxylates such as an acetate, a lactate, a citrate, an oxalate, a glutarate, a malate, a tartrate, a fumarate, a mandelate, a maleate, a benzoate, a phthalate, and the like; organic sulfonates such as a methanesulfonate, an ethanesulfonate, a benzenesulfonate, a p-toluenesulfonate, a camphorsulfonate, and the like.
  • organic carboxylates such as an acetate, a lactate, a citrate, an oxalate, a
  • compound 1 is designated 17-cyclopropylmethyl-3,14 ⁇ -dihydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-indolomorphinan in which R 1 is cyclopropylmethyl, R 2 and R 3 are each hydroxy, R 4 is hydrogen, and m is 0.
  • compound 2 is designated 17-cyclopropylmethyl-3,14 ⁇ -dihydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-(6',7'-benzoindolo)morphinan in which R 1 is cyclopropylmethyl, R 2 and R 3 are each hydroxy, R 4 is hydrogen, m is 2, and two R 5 groups are substituents at the 6' and 7'-positions of the indole ring and form a benzo ring together as the fused ring structure A.
  • compound 3 is designated 17-cyclopropylmethyl-3,14 ⁇ -dihydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-(5',6"-ethano-6',7'-benzoindolo)morphinan in which R 1 is cyclopropylmethyl, R 2 and R 3 are each hydroxy, R 4 is hydrogen, m is 3, two R 5 groups are substituents at the 6' and 7'-positions of the indole ring and form a benzo ring substituted by one R 10 together as the fused ring structure A, and the residual one R 5 is R 11 as a substituent at the 5'-position of the indole ring forms an ethano structure as a bridged structure R 10 -R 11 together with R 10 as a substituent at the 6"-position of the benzene ring adjacent to R 11 with the ring junction therebetween.
  • the compounds represented by formula (I) of the present invention are generally produced by indole synthesis reaction using a ketone compound represented by formula (V) and a phenylhydrazine derivative presented by formula VI), as shown by Scheme 1.
  • ketone compounds represented by formula (V) compounds in which both of R 2 and R 3 are hydroxy, and R 1 is hydrogen, methyl, allyl and cyclopropylmethyl are generally known as noroxymorphone, oxymorphone, naloxone, and nartrexone, respectively, and a compound in which R 2 is hydroxy, R 3 is methoxy, and R 1 is hydrogen is generally known as noroxycodone.
  • Ketone compounds (V) in which R 1 is a group other than the above can be prepared from noroxymorphone or noroxycodone in which R 1 is hydrogen by using the method disclosed in the document [J. Med. Chem., Vol. 35, 4329 (1992).] or the like.
  • such ketone compounds can be prepared by alkylation reaction using alkyl halide R 1 -X 1 (wherein X 1 represents chloro, bromo, iodo, or p-toluenesulfonyloxy) in the presence of an appropriate base, as shown by the formula on the upper right of Scheme 2.
  • the compounds of formula (I) can be produced by indole synthesis reaction using the thus-obtained ketone compounds represented by formula (V).
  • compounds (I) of the present invention can also be produced by any one of methods (1), (2) and (3) below using compounds of the present invention (R 2 , R 3 , R 4 , R 5 and m are defined as the same as the above) represented by formula (I') in which R 1 is hydrogen obtained by indole synthesis reaction using the above ketone compounds (V')
  • the compounds (I) of the present invention can also be produced from the ketone compounds (wherein R 2 and R 3 are defined as the same as the above) represented by formula (V') in which R 1 is hydrogen, by a method (1) of alkylation reaction using an alkyl halide R 1 -X 1 (wherein X 1 is defined as the same as the above) in the presence of an appropriate base, a method (2) of reductive amination using an appropriate aldehyde R 1 '-CHO (wherein R 1 ' represents a group obtained by removing a methylene terminal from R 1 ) and a reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride, or the like, or hydrogenation reaction, or a method (3) comprising amidation using an appropriate acid chloride R1'-CO-Cl (wherein R1' is defined as the same as the above) according to a general method, and then reduction of the amide using a reducing
  • indole synthesis reaction can generally be effected in the presence of an appropriate acid according to demand in an appropriate solvent.
  • the solvent include alcoholic solvents such as methanol, ethanol, and the like; organic carboxylic acid solvents such as formic acid, acetic acid, propionic acid, and the like; polar aprotic solvents such as DMF, DMSO, and the like; hydrocarbon solvents such as benzene, toluene, and the like.
  • alcoholic solvents and organic acid solvents are preferably used, and the use of ethanol or acetic acid produces sufficiently satisfactory results.
  • acids include a wide range of acids such as inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and the like; organic carboxylic acids such as formic acid, acetic acid, propionic acid, and the like; organic sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and the like; Lewis acids such as zinc chloride, phosphorus trichloride, and the like.
  • inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and the like
  • organic carboxylic acids such as formic acid, acetic acid, propionic acid, and the like
  • organic sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and the like
  • Lewis acids such as zinc chloride, phosphorus trichloride, and
  • hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and zinc chloride are proferably used, and particularly hydrochloric acid, sulfuric acid, methanesulfonic acid, and acetic acid which can also be used as a solvent are preferable.
  • phenylhydrazine derivatives can be used in this method without any treatment, but the phenylhydrazine derivatives can also be prepared from corresponding nitrobenzene derivatives (VII) (R 5 and m are defined as the same as the above) or aniline derivatives (VIII) (R 5 and m are defined as the same as the above).
  • nitrobenzene derivatives (VII) are generally led to aniline derivatives (VIII) by hydrogenation reaction or general reduction of nitro groups using a metal hydride reducing agent, a metal, a metal halide or the like.
  • the aniline derivatives are diazotized by reaction with a nitrite such as sodium nitrite under acidic conditions of hydrochloric acid, sulfuric acid, acetic acid, or the like, followed by reduction with tin chloride, iron chloride, tin, iron, zinc, sodium sulfite, sodium thiosulfate, or the like under the similar acidic conditions to the above, as shown by the lower formula (a) in Scheme 4.
  • a nitrite such as sodium nitrite under acidic conditions of hydrochloric acid, sulfuric acid, acetic acid, or the like
  • phenylhydrazine derivatives can also be prepared by the method disclosed in the document [Synthesis, 1 (1977)], which uses an amination agent such as o-mesitylenesulfonylhydroxylamine or the like, as shown by the lower formula (b) in Scheme 3.
  • the phenylhydrazine derivatives (VIa) can also be prepared from halogenated benzene derivatives (IX) (wherein X 2 represents chloro or bromo, and R 5 and m are defined as the same as the above), as shown in Scheme 5.
  • Another method is the method disclosed in the document [Tetrahedron Lett., Vol.
  • the dialkyl azodicarboxylate in which R 21 is ethyl is used.
  • bis(alkoxycarbonyl)phenylhydrazine derivatives (XI) can be hydrolyzed under either of acidic or basic conditions, hydrolysis is preferably effected under acidic conditions, and acidic conditions of hydrochloric acid are preferably used.
  • bis(alkoxycarbonyl)phenylhydrazine derivatives (XI) can be used directly in indole synthesis reaction effected under acidic conditions in the same manner as phenylhydrazine derivatives (VIa).
  • the preparation method is appropriately selected from the above several methods of preparing phenylhydrazine derivatives (VIa) in accordance with availability, reactivity, reaction sensitivity of substituent R 5 of the starting materials.
  • R 4 is R 4d representing (CH 2 ) i -R 16 (i is defined as the same as the above) wherein R 16 is NR 7 R 7' , or cyano (R7 and R7' are defined as the same as the above)
  • R 4 is hydrogen
  • R 4d -X 3 wherein X 3 represents chloro, bromo, iodo, methanesulfonyloxy, trifluoromethanesulfonyloxy benzenesulfonyloxy, or p-toluenesulfonyloxy
  • This substituent can be carried out by using an alkylation agent R 4d -X 3 in which X 3 is generally chloro, bromo, iodo, or p-toluenesulfonyloxy under conditions for alkylation reaction.
  • sodium hydroxide, potassium hydroxide, sodium alkoxide, potassium alkoxide, sodium hydride, potassium hydride, butyllithium, and the like can be used.
  • solvent hydrocarbon solvents such as benzene, toluene, and the like; halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, and the like; ether solvents such as diethyl ether, THF, DME, dioxane, and the like, alcohol solvents such as methanol, ethanol, and the like; polar aprotic solvents such as DMF, DMSO, and the like can be used.
  • Preferred combinations of these bases and solvents include conditions using a phase transfer catalyst such as tetrabutylammonium hydrogensulfate, tetrabutylammonium bromide, or the like, and if required, crown ether, in a two-layer solvent system comprising an aqueous solution of sodium hydroxide or potassium hydroxide, and benzene, toluene, or dichloromethane, conditions using powdered sodium hydroxide or potassium hydroxide in a solvent of DMF or DMSO, and conditions using .sodium hydride in a solvent of THF, DMF, DMSO, or the like.
  • a phase transfer catalyst such as tetrabutylammonium hydrogensulfate, tetrabutylammonium bromide, or the like, and if required, crown ether
  • a phase transfer catalyst such as tetrabutylammonium hydrogensulfate, tetrabutylammonium bromide,
  • phase transfer catalyst such as tetrabutylammonium hydrogensulfate, tetrabutylammonium bromide, or the like in a two-layer solvent system comprising an aqueous solution of sodium hydroxide or potassium hydroxide, and benzene, toluene, or dichloromethane, or the conditions using powdered sodium hydroxide or potassium hydroxide in a solvent of DMF or DMSO.
  • R 4d is (CH 2 ) i -R 16 (i is defined as the same as the above) wherein R 16 is NR 7 R 7 ', and particularly, both R 7 and R 7 ' are hydrogen are defined as the following formula (Id1) (R 1 , R 2 , R 3 , R 5 and m are defined as the same as the above).
  • compounds (Y represents O or S, and R 1 , R 2 , R 3 , R 5 and m are defined as the same as the above) represented by formula (Ie) in which R 4 is R 4e representing (CH 2 ) i -R 16 (i is defined as the same as the above) wherein R 16 is isocyanato or isothiocyanato can be produced by converting compounds represented by formula (Id1) to isocyanate or thioisocyanate, for example, as shown by Scheme 11.
  • Conversion to isocyanate can be carried out by using phosgene or triphosgene in a solvent such as benzene, toluene, pyridine, ethanol, dichloromethane, chloroform or the like in accordance with an ordinary method.
  • a solvent such as benzene, toluene, pyridine, ethanol, dichloromethane, chloroform or the like in accordance with an ordinary method.
  • Conversion to isothiocyanate can be carried out by a method using thiophosgene in a solvent such as benzene, toluene, dichloromethane, chloroform, or acetone, or a two-layer solvent system comprising a basic aqueous solution of sodium hydroxide, sodium bicarbonate, or the like, and dichloromethane, chloroform, or the like, or a method using di(2-pyridyl) thionocarbonate in dichloromethane [Tetrahedron Lett., Vol. 26, 1661 (1985)].
  • Condenstion with carboxylic acid chloride R 9 -CO-Cl, carboxylic acid anhydride (R 9 -CO) 2 O, chloroformate ester R 9 O-CO-Cl or chlorothionoformate ester R 9 O-CS-Cl can be carried out by using, as a base, a tertiary amine such as triethylamine, diisopropylethylamine, proton sponge, or the like, an organic base such as pyridine, dimethylaminopyridine, imidazole, or the like, an inorganic base such as potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, or the like in a solvent such as a halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or the like; an ether solvent such as an ether, THF, DME, dioxane, or the like;
  • carboxylic acid chloride chloroformate ester or chlorothionoformate ester
  • conditions using triethylamine in dichloromethane or chloroform, or conditions using potassium carbonate, sodium carbonate or sodium bicarbonate in a THF-water solvent mixture are preferably used.
  • conditions using pyridine as both a base and a solvent are preferably used.
  • Condensation with carboxylic acid R9-COOH can generally be carried out by using any one of general known condensation agents.
  • condensation agents such as N,N'-dicyclohexylcarbodiimide (abbreviated to “DCC” hereinafter), 1,1'-carbonyldiimidazole (abbreviated to “CDI” hereinafter), bis-(2-oxo-3-oxazolidinyl)phosphinic acid chloride (abbreviated to "BOPCl” hereinafter), and the like are preferably used.
  • condensation can be carried out by using, as a base, a tertiary amine such as triethylamine, diisopropylethylamine, proton sponge, or the like, an organic base such as pyridine, dimethylaminopyridine, imidazole, or the like, in a reaction solvent such as a halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or the like, an ether solvent such as an ether, THF, DME, dioxane, or the like.
  • a reaction solvent such as a halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or the like
  • an ether solvent such as an ether, THF, DME, dioxane, or the like.
  • dimethylaminopyridine is preferably used in dichloromethane or chloro
  • an ether solvent such as an ether, THF, DME, dioxane, or the like
  • a halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or the like
  • THF is preferably used.
  • a halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or the like
  • an ether solvent such as ether, THF, DME, dioxane, or the like
  • a base a tertiary amine such as triethylamine, diisopropylethylamine, proton sponge, N-ethylpiperidine, or the like
  • an organic base such as pyridine, dimethylaminopyridine, imidazole, or the like
  • N-ethylpiperidine is preferably used in dichloromethane or chloroform.
  • Condensation with isocyanate R 9 -NCO or isothiocyanate R 9 -NCS can be carried out directly in a halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or the like; an ether solvent such as an ether, THF, DME, dioxane, or the like. Particularly, chloroform is preferably used.
  • Compounds represented by formula (If4) can be produced directly by formylation using formic acid or formate (methyl or ethyl ester).
  • formylation methods such as a method using formic acid and acetic anhydride, a method using formate and a base such as triethylamine, or the like, a method using mixed acid anhydride such as mixed formic, mixed acetic anhydride or the like, a method using DMF and phosphorus oxychloride or sodium methoxide, etc.
  • Hydrolysis reaction can be effected by using as a base an inorganic base such as, potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, or the like, particularly potassium carbonate or sodium hydroxide, in water, an alcohol solvent such as methanol, ethanol, or the like, an ether solvent such as an ether, THF, DME, dioxane, or the like, or a solvent mixture thereof.
  • a base an inorganic base such as, potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, or the like, particularly potassium carbonate or sodium hydroxide, in water, an alcohol solvent such as methanol, ethanol, or the like, an ether solvent such as an ether, THF, DME, dioxane, or the like, or a solvent mixture thereof.
  • a halogenated hydrocarbon solvent such as dichloromethane, chloroform, or the like is appropriately added.
  • the condensation reaction can be generally effected directly in a halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or the like, an ether solvent such as an ether, THF, DME, dioxane, or the like.
  • a halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or the like
  • an ether solvent such as an ether, THF, DME, dioxane, or the like.
  • demethylation reaction can be effected by a method using boron tribromide [Document: Tetrahedron, Vol. 24, 2289 (1968)] or boron trichloride in a solvent such as dichloromethane, chloroform, or 1,2-dichloroethane, a method using thioalkoxide, particularly sodium thioethoxide [Document: Tetrahedron Lett., 1327 (1970)] in DMF, or the like.
  • compounds (R 1 , R 2 , R 4 , R 5 and m are defined as the same as the above) represented by formula (Ii) wherein R 3 is methoxy can also be produced by methylation of phenolic hydroxy groups of compounds (R 1 , R 2 , R 4 , R 5 and m are defined as the same as the above) represented by formula (Ij) wherein R 3 is hydroxy by a general method, as shown in Scheme 16.
  • methylation particularly, a method using methyl iodide in a solvent such as DMF or acetone in the presence of an inorganic base such as sodium carbonate, potassium carbonate, lithium carbonate, or the like, a method using diazomethane in a solvent such as diethyl ether or the like in the presence of silica gel, and the like are preferably used.
  • the indolomorphinan derivatives of the present invention represented by formula (I) exhibit excellent effects on disorders of the cerebral nerve cells, as described in the examples below. Therefore, the compounds of the present invention can be used as agents for curing and preventing cerebral disorders, i.e., medicines useful for ameliorating various cerebral diseases and aftereffects thereof, and preventing recurrence thereof. Specifically, it was made apparent that the compounds of the present invention can be used as therapeutic agents for cerebral stroke, therapeutic agents for traumatic cerebral diseases, therapeutic agents for cerebral edema, therapeutic agents for ischemic diseases, therapeutic agents for cerebral neurodegenerative diseases, and therapeutic agents for aftereffects of cerebral diseases.
  • the compounds of the present invention exhibited the excellent neuroprotetive action on damages of the cerebral nerve cells, and it was thus found that the compounds of the present invention are useful as cerebral neuroprotective agents which inhibit ischemic or hemorrhagic cerebrovascular diseases, traumatic cerebral diseases and various cerebral neurodegenerative diseases by the protecting action on the cerebral nerve cells.
  • the therapeutic agents for cerebral stroke are medicines used for curing, ameliorating or preventing ischemic or hemorrhagic cerebral stroke, specifically, cerebral infarction (cerebral embolism, cerebral thrombosis), cerebral hemorrhage, subarachnoid hemorrhage, transient ischemic attack (TIA), hypertensive encephalophathy, etc.
  • the therapeutic agents for traumatic cerebral diseases are medicines used for ameliorating cerebral disorder caused by trauma and functional disorder of the brain accompanied thereby, and ameliorating aftereffects.
  • the therapeutic agents for cerebral edema are medicines used for ameliorating, curing or preventing cerebral edema caused by a lesion of hemorrhage, infaction, tumor, trauma, or the like which occurs in the brain, or an increase in intracranial pressure to ameliorate disorders of the cerebral nerve cells due to cerebral edema.
  • the therapeutic agents for ischemic diseases are medicines used for curing, emeliorating or preventing the cerebral disorders caused by insufficient supply of oxygen and glucose to the cerebral nerve cells on the basis of ischemia due to hypoxia, hypoglycemia, drug poisoning, or the like.
  • the therapeutic agents for cerebral neurodegenerative diseases are medicines used for curing, ameliorating or preventing cerebral diseases such as Alzheimer's disease, Parkinson's disease, Huntington's chorea, diffuse Lewy's bodies, Creutzfeldt-Jakob's disease, and the like, which cause disorders of the cerebral nerve cells accompanied with degeneration of the nerve cells.
  • the therapeutic agents for aftereffects of cerebral diseases are medicines used for curing, ameliorating or preventing aftereffects caused by the above cerebral disorders, such as cerebrovascular dementia, amnesia, disorder of consciousness, motor paralysis, allophasis, sensory disorder, mental disorder, memory disorder, and the like.
  • a free base or salt thereof may be used, and additives such as an excipient, a stabilizer, a preservative, a buffer, a solubilizer, an emulsifier, a diluent, an isotonizing agent, etc. may be appropriately mixed.
  • additives such as an excipient, a stabilizer, a preservative, a buffer, a solubilizer, an emulsifier, a diluent, an isotonizing agent, etc.
  • parenteral administration or oral administration produces sufficient effects.
  • Administration formulations include an injection, a tablet, a liquid, a capsule, granules, a powder, and the like, and these formulations can be produced by known formulation techniques.
  • the dosage is appropriately selected in accordance with the symptoms, age and body weight of a patient, the administration method, etc.
  • the amount of the effective component per adult is 0.0001 mg to 10 g per day, preferably 0.001 mg to 1 g per day, and the agent can be administered once or divided into several doses.
  • Indole synthesis reaction was effected by using nartrexone as a raw material in accordance with the method of Reference Example 1. Namely, 17-cyclopropylmethyl-3,14 ⁇ -dihydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-(1'-phenylindolo)morphinan 4 was obtained by using 1,1-diphenylhydrazine in place of phenylhydrazine.
  • 17-cyclopropylmethyl-3,14 ⁇ -dihydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-(6'-cyclohexylindolo)morphinan 5 was obtained by using 3-cyclohexylphenylhydrazine (prepared from 3-cyclohexylaniline).
  • 17-cyclopropylmethyl-3,14 ⁇ -dihydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-(4'-heptylindolo)morphinan 6 and 17-cyclopropylmethyl-3,14 ⁇ -dihydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-(6'-heptylindolo)morphinan 7 were obtained by using 3-heptylphenylhydrazine (prepared from 3-heptylaniline).
  • 17-cyclopropylmethyl-3,14 ⁇ -dihydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-(6',7'-benzoindolo)morphinan 2 and 17-cyclopropylmethyl-3,14 ⁇ -dihydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-(4',5'-benzoindolo)morphinan 8 were obtained by using 1-naphthylhydrazine (prepared from 1-bromonaphthalene).
  • 17-cyclopropylmethyl-3,14 ⁇ -dihydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-(3"-chloro-6',7'-benzoindolo)morphinan 12 was obtained by using 8-chloro-1-naphthylhydrazine (prepared from 8-chloro-1-aminonaphthalene).
  • indole synthesis reaction was effected by using 17-cyclopropylmethyl-6-oxy-4,5 ⁇ -epoxy-3-methoxy-14 ⁇ -hydroxymorphinan (nartrexone-3-methyl ether) as a raw material in place of nartrexone, and 4-t-butylphenylhydrazine (prepared from 4-t-butylaniline) and 1-naphthylhydrazine as hydrazine derivatives to obtain 17-cyclopropylmethyl-3-methoxy-14 ⁇ -hydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-(5'-t-butylindolo)morphinan 16 and 17-cyclopropylmethyl-3-methoxy-14 ⁇ -hydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-(6',7'-benzoindolo)morphinan 17 , respectively.
  • indole synthesis reaction was effected by using 17-cyclopropylmethyl-6-oxy-4,5 ⁇ -epoxy-14 ⁇ -hydroxymorphinan as a raw material in place of nartrexone, and 1-naphthylhydrazine as a hydrazine derivative to obtain 17-cyclopropylmethyl-14 ⁇ -hydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-(6',7'-benzoindolo)morphinan 18 .
  • Indole synthesis reaction was effected by using natrexone as a raw material in accordance with the method of Reference Example 1. Namely, 5-hydrazinoacenaphthene (prepared from 5-nitroacenaphthene), 3-hydrazinofluoranthene (prepared from 3-aminofluoranthene), 1-hydrazinofluorene (prepared from 1-aminofluorene), 1-hydrazinoanthracene (prepared from 1-aminoanthracene), 4-hydrazinofluorene (prepared from 4-acetoamino-9-fluorenone), 9-hydrazinophenanthrene (prepared from 9-bromophenanthrene), 1-phenylpyrazoline (prepared by the method disclosed in J.
  • indole synthesis reaction was effected by using 6-oxy-4,5 ⁇ -epoxy-3-methoxy-14 ⁇ -hydroxymorphinan (noroxycodone) as a raw material in place of nartrexone, and 1-naphthylhydrazine as a hydrazine derivative.to obtain 3-methoxy-14 ⁇ -hydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-(6',7'-benzoindolo)morphinan 28 .
  • the thus-obtained crude product was purified by silica gel column chromatography (ammonia saturated chloroform ⁇ ammonia saturated chloroform-methanol (100:1 ⁇ 40:1)) to obtain 412 mg (yield 50 %) of title compound.
  • the compound was recrystallized from methanol to obtain 140 mg of crystal.
  • the extract was dried with 30 ml of saturated brine, dried and then concentrated.
  • the compound was dissolved in 10 ml of methanol and 5 ml of chloroform, and 34.1 ⁇ l of methanesulfonic acid was added to the resultant solution to form methanesulfonate. After evaporation of methanol solution 5 ml x 2, the product was suspended in ether, and then filtered off to obtain 251 mg (yield 73 %) of title compound.
  • 17-cyclopropylmethyl-3,14 ⁇ -dihydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-indolomorphinan 1 was used as a raw material in place of 17-cyclopropylmethyl-3,14 ⁇ -dihydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-(5'-methyl-6',7'-benzoindolo)morphinan 13 to obtain 17-cyclopropylmethyl-3-methoxy-14 ⁇ -hydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-indolomorphinan 33 .
  • methyl iodide was used as an alkylation agent in place of 2-phenylethyl p-toluenesulfonate to obtain 17-cyclopropylmethyl-3-methoxy-14 ⁇ -hydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-[1'-methyl-6',7'-benzoindolo]morphinan 42 .
  • 17-cyclopropylmethyl-3-methoxy-14 ⁇ -hydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-indolomorphinan 33 was used as a raw material in place of 17-cyclopropylmethyl-3-methoxy-14 ⁇ -hydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-(6',7'-benzoindolo)morphinan 17 , and benzyl chloride was used as an alkylation agent to obtain 17-cyclopropylmethyl-3-methoxy-14 ⁇ -hydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-(1'-benzylindolo)morphinan 43 .
  • 17-cyclopropylmethyl-3,14 ⁇ -dihydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-[1'-(3-aminopropyl)-6',7'-benzoindolo]morphinan 25 was used as a raw material in place of 17-cyclopropylmethyl-3,14 ⁇ -dihydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-[1'-(3-aminopropyl)indolo]morphinan 24 to obtain 17-cyclopropylmethyl-3,14 ⁇ -dihydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-[1'-(3-isothiocyanatopropyl)-6',7'-benzoindolo)morphinan 60 .
  • 6-phenylhexanoyl chloride and 3-trifluoromethylcinnamoyl chloride were used as acylation agents in place of benzoyl chloride to obtain 17-cyclopropylmethyl-3,14 ⁇ -dihydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-[1'-[3-(6-phenylhexanoamido)propyl]indolo]morphinan 62 , and 17-cyclopropylmethyl-3,14 ⁇ -dihydroxy-6,7-dehydro-4,5 ⁇ -epoxy-6,7,2',3'-[1'-[3-(3-trifluoromethylcinnamido)propyl]indolo] morphinan 63 , respectively.
  • a compound having the action to protect the nerve cells from the cytotoxicity of glutamic acid exhibits the action to inhibit various ischemic, hemorrhagic or traumatic cerebral disorders, and disorders of the cerebral nerve cells caused by various nerve degenerations, and is useful as an agent for curing and preventing cerebral stroke, traumatic cerebral diseases, cerebral edema, and cerebral neurodegenerative diseases by protecting the cerebral nerve cells from these disorders.
  • This action was evaluated by using the in vitro evaluation system which will be described below.
  • a fetus was taken from the abdomen of a Wistar female rat on the 18 to 19th day of pregrancy under aspetic conditions, and the head of the fetus was opened to extract the brain.
  • the brain was placed in an ice-cooled L-15 medium, and the cerebral cortex was separated under a microscope.
  • the cerebral cortexes of about 30 rats were cut into pieces, and then suspended in 10 ml of a 0.25% trypsin solution and 0.2 ml of a 0.01% DNase solution, followed by culture at 37° C for 30 minutes. Then, 2 ml of serum was added to the solution, and immediately the resultant mixture was centrifuged at 1200 rpm for 2 minutes to separate the precipitates.
  • a DF medium a medium obtained by adding 20 nM of transferrin, 5 ⁇ g/ml of insulin, 20 nM of progesterone, 60 nM of selenite, 50 U/ml of penicillin, and 50 U/ml of streptmycin to a mixture of equivalent amounts of Dulbecco modified Eagle medium and F-12 medium
  • 20 pipetting operations using a 10-ml plastic pipette to obtain a cell suspension.
  • the cell suspension was filtered with nylon mesh (pore diameter 43 pm) to fractionate isolated cells.
  • the thus-obtained isolated cells were diluted with a DF medium to a concentration of 6.0 x 10 5 cells/ml, and 500 ⁇ l of the diluted cells was inoculated in each of the 48 wells of a 48-well culture plate precoated with polylysine, followed by culture at 37°C for 1 day in the presence of 5% of CO 2 .
  • the medium was changed to a new DF medium, and 10 ⁇ l of a solution of 0.5M glutamic acid in distilled water was added to each of the wells (the final glutamic acid concentration was 10 mM), followed by further culture at 37°C for 24 hours in the presence of 5% of CO 2 .
  • test compound was dissolved in distilled water, 10% or 100% DMSO or 10% methanol, and 5 ⁇ l of the solution was added to each of the wells immediately before glutamic acid was added.
  • enzyme activity of lactic acid dehydrogenase (LDH) leaking from the damaged cells into the medium was measured.
  • LDH leakage was measured at each of concentrations to determine a dose-response curve by the modified Cochran-Armitige method.
  • the 50% effective dose (ED 50 ) of each of the test compounds was determined from the curve. The results are shown in Table 1.
  • the compounds 2-9, 11-15, 17-20, 22, and 68-72 are reference examples.
  • the compounds of the present invention have the action to protect the nerve cells from the cytotoxicity of glutamic acid, and are useful as agents for curing and preventing cerebral stroke, traumatic cerebral diseases, cerebral edema, and cerebral neurodegenerative diseases.
  • MCAo middle cerebral artery occlusion
  • the common carotid artery was incised, and the embolus was inserted from the common carotid artery to the internal carotid artery by about 15 to 16 mm, and ligated and fixed to the internal carotid artery by the silk yarn at the end thereof near the nylon yarn.
  • the end of the embolus was inserted into the anterior cerebral artery by about 1 to 2 mm beyond the middle cerebral artery bifurcation, and the inlet of the middle cerebral artery was occluded by the body (resin part) of the embolus for 1 hour.
  • the embolus with a yarn was removed to recirculate the blood flow to the middle cerebral artery.
  • the infarction volume was compared with the infarction volume of a control group to calculate the rate of inhibition of infarction.
  • the results obtained are shown in Table 2.
  • Action to inhibit infarction in rat model of middle cerebral artery ischemia Compound Rate of inhibition of infarction (%) Compound Rate of inhibition of infarction (%) Compound Rate of inhibition of infarction (%) 1 23 17 56 70 34 2 72 18 23 72 85 3 54 19 29 73 34 5 31 20 10 74 27 6 33 23 79 75 30 8 49 25 15 76 65 9 9 61 29 10 15 62 10 12 67 66 25 14 29 67 39 16 22 69 69
  • the compounds of the present invention have the action to protect the cerebral nerve cells from various damages caused by occurrence of cerebral ischemia to inhibit evolution of infarction, and the action to prevent increase in disease conditions of cerebral infarction. Therefore, it was found that the compounds of the present invention are useful as agents for curing and preventing cerebral stroke, traumatic cerebral diseases, cerebral edema, and cerebral neurodegenerative diseases.
  • the compounds of the present invention are useful as agents for curing or preventing cerebral disorders. Namely, it was apparent that the compounds of the present invention can be used as medicines useful for curing and preventing cerebral stroke, traumatic cerebral diseases, cerebral edema, and cerebral neurodegenerative diseases by inhibiting various ischemic, hemorrhagic or traumatic cerebral disorders, and damages of the cerebral nerve cells caused by various nerve degenerations to protect the cerebral nerve cells.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (7)

  1. Indolmorphinanderivat oder pharmakologisch akzeptables Säureadditionssalz davon, repräsentiert durch die folgende Formel (I):
    Figure 01680001
    [worin R1 einen Wasserstoff, ein Alkyl, das 1 bis 5 Kohlenstoffatome hat, ein Cycloalkylalkyl, das 4 bis 7 Kohlenstoffatome hat, ein Cycloalkenylalkyl, das 5 bis 7 Kohlenstoffatome hat, ein Aryl, das 6 bis 12 Kohlenstoffatome hat, ein Aralkyl, das 7 bis 13 Kohlenstoffatome hat, ein Alkenyl, das 2 bis 7 Kohlenstoffatome hat, ein Furan-2-ylalkyl (wobei eine Alkylhälfte 1 bis 5 Kohlenstoffatome hat) oder ein Thiophen-2-ylalkyl (wobei eine Alkylhälfte 1 bis 5 Kohlenstoffatome hat) repräsentiert;
    R2 und R3 unabhängig einen Wasserstoff, ein Hydroxy, ein Alkoxy, das 1 bis 5 Kohlenstoffatome hat, ein Alkanoyloxy, das 1 bis 5 Kohlenstoffatome hat, ein Aralkyloxy, das 7 bis 13 Kohlenstoffatome hat, oder ein Arylcarbonyloxy, das 7 bis 13 Kohlenstoffatome hat, repräsentieren;
    R4 (CH2)1-R16 repräsentiert;
    R15 ein Fluor, ein Chlor, ein Brom, ein Jod, ein Nitro, ein Amino, ein Hydroxy, ein Alkyl, das 1 bis 5 Kohlenstoffatome hat, ein Alkoxy, das 1 bis 5 Kohlenstoffatome hat, ein Isothiocyanat, ein Trifluormethyl, ein Trifluormethoxy oder ein Cyano repräsentiert;
    i eine ganze Zahl von 1 bis 8 repräsentiert;
    R16 NR7R7', ein Nitro, ein Cyano, ein Isocyano, ein Isocyanat, ein Isothiocyanat, CONR7R7', NR7CHO, NR7(CO)-R9, NR7(CO)NR8R9, NR7(C=S)NR8R9, NR7(CO)O-R9 oder NR7(C=S)O-R9 (worin R7, R7' und R8 unabhängig einen Wasserstoff oder ein Alkyl, das 1 bis 5 Kohlenstoffatome hat, repräsentieren) repräsentiert; und
    R9 ein Alkyl, das 1 bis 5 Kohlenstoffatome hat, ein Aryl, das 6 bis 12 Kohlenstoffatome hat (das mit wenigstens einem Substituenten R15 substituiert sein kann), ein Heteroaryl, das eine Anzahl von 1 bis 3 Heteroatomen und 3 bis 11 Kohlenstoffatome hat (wobei ein Heteroatom O, N oder S ist und es mit wenigstens einem Substituenten R15 substituiert sein kann), ein Aralkyl, das 7 bis 13 Kohlenstoffatome hat (das mit wenigstens einem Substituenten R15 substituiert sein kann) oder ein Arylalkenyl, das 8 bis 15 Kohlenstoffatome hat (wobei die Arylhälfte mit wenigstens einem Substituenten R15 substituiert sein kann) repräsentiert;
    m eine ganze Zahl von 0 bis 4 repräsentiert;
    R5 R11 oder zwei R5 repräsentiert, die an benachbarten Kohlenstoffatomen substituiert sind und zusammen eine fusionierte Ringstruktur A bilden (wobei die verbleibenden 0 bis 2 Substituenten R5 jeweils R11 repräsentieren oder eine weitere fusionierte Ringstruktur A bilden);
    die fusionierte Ringstruktur A eine Benzo-, eine Indeno- oder eine Naphthostruktur repräsentiert, die nicht-substituiert oder mit 1 bis 4 Substituenten R10 substituiert ist;
    R10 und R11 unabhängig (1) ein Fluor, ein Chlor, ein Brom, ein Jod, ein Nitro, ein Alkyl, das 1 bis 8 Kohlenstoffatome hat, ein Alkoxy, das 1 bis 5 Kohlenstoffatome hat, ein Isothiocyanat, ein Trifluormethyl, ein Trifluormethoxy, ein Cyano, ein Phenyl, ein Hydroxyalkyl, das 1 bis 3 Kohlenstoffatome hat, SR12, SOR12, SO2R12, (CH2)kCO2R12, SO2NR13R14, CONR13R14, (CH2)kNR13R14 oder (CH2)kN(R13)COR14 (wobei k eine ganze Zahl von 0 bis 5 repräsentiert, R12 ein Alkyl, das 1 bis 5 Kohlenstoffatome hat, repräsentiert und R13 und R14 unabhängig einen Wasserstoff ein Alkyl, das 1 bis 5 Kohlenstoffatome hat, oder ein Cycloalkylalkyl, das 4 bis 6 Kohlenstoffatome hat, repräsentieren) repräsentieren und/oder (2) R10 und R11 an benachbarten Kohlenstoffatomen mit einer Ringverzweigung dazwischen substituiert sind, wobei sie zusammen irgendeine der überbrückten Ethano-, Propano und o-Benzenostrukturen R10-R11 bilden; und
    die Formel (I) die (+)-Form, die (-)-Form und (+/-)-Form mit einschließt].
  2. Indolmorphinanderivat oder pharmakologisch akzeptables Säureadditionssalz davon nach Anspruch 1, wobei in Formel (I) R5 R11 ist, welcher unhabhängig ein Fluor, ein Chlor, ein Brom, ein Jod, ein Nitro, ein Alkyl, das 1 bis 8 Kohlenstoffatome hat, ein Alkoxy, das 1 bis 5 Kohlenstoffatome hat, ein Isothiocyanat, ein Trifluormethyl, ein Trifluormethoxy, ein Cyano, ein Phenyl, ein Hydroxyalkyl, das 1 bis 3 Kohlenstoffatome hat, SR12, SOR12, SO2R12, (CH2)kCO2R12, SO2NR13R14, CONR13R14, (CH2)kNR13R14 oder (CH2)kN(R13)COR14 (wobei k, R12, R13 und R14 genauso definiert sind wie in Anspruch 1) repräsentiert.
  3. Indolmorphinanderivat oder pharmakologisch akzeptables Säureadditionssalz davon nach Anspruch 1, wobei in Formel (I) m eine ganze Zahl von 2 bis 4 ist, zwei R5-Gruppen zusammen eine fusionierte Ringstruktur A bilden und die verbleibenden 0 bis 2 R5-Gruppen jeweils R11 sind oder zusammen eine weitere fusionierte Ringstruktur A bilden (A und R11 sind genauso definiert wie in Anspruch 1).
  4. Indolmorphinanderivat oder pharmakologisch akzeptables Säureadditionssalz davon nach Anspruch 3, wobei in Formel (I) m eine ganze Zahl von 2 bis 4 ist, zwei R5-Gruppen zusammen eine fusionierte Ringstruktur A bilden, die eine Benzostruktur ist, und die verbleibenden 0 bis 2 R5-Gruppen jeweils R11 sind (R11 ist genauso definiert wie in Anspruch 1).
  5. Indolmorphinanderivat oder pharmakologisch akzeptables Säureadditionssalz davon nach Anspruch 3, wobei in Formel (I) m eine ganze Zahl von 2 bis 4 ist, zwei R5-Gruppen zusammen eine fusionierte Ringstruktur A bilden, die eine Indeno- oder Naphtostruktur ist, und die verbleibenden 0 bis 2 R5-Gruppen jeweils R11 sind (R11 ist genauso definiert wie in Anspruch 1).
  6. Indolmorphinanderivat oder pharmakologisch akzeptables Säureadditionssalz davon nach Anspruch 3, wobei in Formel (I) m 4 ist, zwei R5-Gruppen zusammen eine fusionierte Ringstruktur A bilden und die verbleibenden zwei R5-Gruppen zusammen eine weitere fusionierte Ringstruktur A bilden (A ist genauso definiert wie in Anspruch 1).
  7. Arzneimittel, umfassend ein Indolmorphinanderivat oder pharmakologisch akzeptables Säureadditionssalz davon, repräsentiert durch die Formel (I):
    Figure 01720001
    [wobei R1, R2, R3, R4, m und R5 genauso wie in Anspruch 1 definiert sind und die Formel (I) die (+)-Form, die (-)-Form und (+/-)-Form mit einschließt].
EP98900228A 1997-01-16 1998-01-13 Indolmorphinan-derivate und medikamente zur behandlung/mittel zur vorbeugung von cerebralen störungen Expired - Lifetime EP0894799B1 (de)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP582997 1997-01-16
JP582997 1997-01-16
JP5829/97 1997-01-16
PCT/JP1998/000092 WO1998031684A1 (fr) 1997-01-16 1998-01-13 Derives d'indolomorphinane et medicaments/remedes preventifs contre les troubles cerebraux

Publications (3)

Publication Number Publication Date
EP0894799A1 EP0894799A1 (de) 1999-02-03
EP0894799A4 EP0894799A4 (de) 2001-08-16
EP0894799B1 true EP0894799B1 (de) 2004-04-07

Family

ID=11621945

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98900228A Expired - Lifetime EP0894799B1 (de) 1997-01-16 1998-01-13 Indolmorphinan-derivate und medikamente zur behandlung/mittel zur vorbeugung von cerebralen störungen

Country Status (12)

Country Link
US (1) US6156762A (de)
EP (1) EP0894799B1 (de)
JP (1) JP4110579B2 (de)
KR (1) KR100557804B1 (de)
CN (1) CN1117754C (de)
AT (1) ATE263769T1 (de)
AU (1) AU739367B2 (de)
DE (1) DE69822937T2 (de)
ES (1) ES2217533T3 (de)
NO (1) NO984263L (de)
NZ (1) NZ331769A (de)
WO (1) WO1998031684A1 (de)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19939044A1 (de) * 1999-08-18 2001-03-15 Gruenenthal Gmbh Verwendung von Morphinanderivaten als Arzneimittel
CN1204139C (zh) * 1999-08-24 2005-06-01 东丽株式会社 神经性疼痛治疗剂
JP2004529161A (ja) 2001-05-04 2004-09-24 トゥラリック インコーポレイテッド 縮合複素環式化合物
US6809104B2 (en) 2001-05-04 2004-10-26 Tularik Inc. Fused heterocyclic compounds
MXPA05004739A (es) 2002-11-06 2005-08-02 Tularik Inc Compuestos heterociclicos fusionados.
US20100172909A1 (en) * 2005-10-24 2010-07-08 Masahiro Nishibori Cerebral edema suppressant
WO2011009020A2 (en) 2009-07-16 2011-01-20 Mallinckrodt Inc. Compounds and compositions for use in phototherapy and in treatment of ocular neovascular disease and cancers
WO2016167318A1 (ja) * 2015-04-16 2016-10-20 学校法人北里研究所 記憶改善剤及びその使用

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4680172A (en) * 1985-03-05 1987-07-14 Ciba-Geigy Corporation Devices and methods for treating memory impairment
US4816586A (en) * 1987-07-29 1989-03-28 Regents Of The University Of Minnesota Delta opioid receptor antagonists
JPH03218313A (ja) * 1989-11-22 1991-09-25 Toray Ind Inc 脳細胞保護剤
JP2906654B2 (ja) * 1989-11-28 1999-06-21 東レ株式会社 免疫抑制剤及びその製造方法
US5223507A (en) * 1992-01-21 1993-06-29 G. D. Searle & Co. Method of using opioid compounds as delta opioid selective agonist analgesics
US5225417A (en) * 1992-01-21 1993-07-06 G. D. Searle & Co. Opioid agonist compounds
US5852030A (en) * 1992-09-29 1998-12-22 Toray Industries, Inc. Indole derivatives, process for producing the same and medicinal uses of the same
CN1043766C (zh) * 1992-09-29 1999-06-23 东丽株式会社 吲哚衍生物及其制法和它们在制备药物中的应用
DE69318710T2 (de) * 1992-12-22 1998-09-10 Toray Industries Antitussivum
EP0661283B1 (de) * 1993-07-19 1998-10-21 Toray Industries, Inc. Wirkstoff zum schutze von gehirnzellen
CA2143864C (en) * 1993-07-23 2006-01-24 Hiroshi Nagase Morphinan derivatives and pharmaceutical use thereof
SE9401728D0 (sv) * 1994-05-18 1994-05-18 Astra Ab New compounds II
SE9401727D0 (sv) * 1994-05-18 1994-05-18 Astra Ab New compounds I

Also Published As

Publication number Publication date
US6156762A (en) 2000-12-05
DE69822937D1 (de) 2004-05-13
ES2217533T3 (es) 2004-11-01
KR20000064618A (ko) 2000-11-06
CN1220668A (zh) 1999-06-23
KR100557804B1 (ko) 2006-06-20
NO984263D0 (no) 1998-09-15
AU739367B2 (en) 2001-10-11
NZ331769A (en) 2000-05-26
EP0894799A4 (de) 2001-08-16
EP0894799A1 (de) 1999-02-03
WO1998031684A1 (fr) 1998-07-23
DE69822937T2 (de) 2004-08-12
CN1117754C (zh) 2003-08-13
JP4110579B2 (ja) 2008-07-02
NO984263L (no) 1998-11-13
AU5343798A (en) 1998-08-07
ATE263769T1 (de) 2004-04-15

Similar Documents

Publication Publication Date Title
CA2494700C (en) Calcium receptor modulating compound and use thereof
EP3470409B1 (de) Alpha und beta-ungesättigte amidverbindung aus benzotriazol als tgf-beta ri-inhibitor
WO2007055418A1 (ja) アザ置換スピロ誘導体
JPH11502859A (ja) ピラゾール誘導体およびその製造法
JP2004517852A (ja) インドール誘導体および５−ｈｔ２ｂおよび５−ｈｔ２ｃ受容体リガンドとしてのそれらの使用
CN105518005A (zh) 作为rock抑制剂的三环吡啶-甲酰胺衍生物
US6087369A (en) Indole derivatives, process for producing the same and medicinal uses of the same
EP0915094A1 (de) Morphinanderivate und ihre medizinische Anwendung
AU650322B2 (en) Imidazopyridine PAF/H1 antagonists
EP0894799B1 (de) Indolmorphinan-derivate und medikamente zur behandlung/mittel zur vorbeugung von cerebralen störungen
AU2017327304B2 (en) Use of morphinan derivative for therapeutic treatment of opioid δ receptor agonist-related disease
CA3202303C (en) Trop2 targeting antibody-drug conjugate, and preparation method and use therefor
RU2200737C2 (ru) Пиримидо[4,5-b]индолы и промежуточное соединение (варианты)
CN111662299B (zh) 一种取代吲哚并氮杂酮类化合物及其制备方法和应用
JP2003520851A (ja) 神経栄養活性を有するイサチン誘導体
EA005071B1 (ru) ЗАМЕЩЕННЫЕ ПИРАЗОЛО[4,3-e]ДИАЗЕПИНЫ, ФАРМАЦЕВТИЧЕСКИЕ КОМПОЗИЦИИ, СОДЕРЖАЩИЕ ИХ, И ПРИМЕНЕНИЕ В КАЧЕСТВЕ ЛЕКАРСТВЕННЫХ ПРОДУКТОВ
JPH11508892A (ja) 抗ガストリン活性を持つ芳香族酸ジアミド類、その製造法および医薬用途
EP0911334A1 (de) Chinolinmorphinan-derivate und ihre medizinische anwendung
TW206230B (de)
EP1097934B1 (de) Lk6-a-derivate
JP2000514075A (ja) ベンゾ［ｇ］キノリン誘導体
CA2249240C (en) Indolomorphinan derivative and agent for curing and preventing cerebral disorder
CN115028648B (zh) 三并环化合物及其药物组合物和应用
WO2022194261A1 (zh) 嘧啶并环类化合物及其用于制备治疗疼痛、脊髓损伤药物中的用途
HU195214B (en) Process for producing 12b-substituted-1-(hydroxymethyl)-octahydro-indolo /2,3-a/ quinolizine derivatives and pharmaceutical preparations comprising these compounds

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19980930

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI NL PT SE

A4 Supplementary search report drawn up and despatched

Effective date: 20010629

AK Designated contracting states

Kind code of ref document: A4

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI NL PT SE

RIC1 Information provided on ipc code assigned before grant

Free format text: 7C 07D 491/18 A, 7A 61K 31/485 B, 7C 07D 489/00 B, 7C 07D 491/20 B, 7C 07D 491/20 J, 7C 07D 307:00 J, 7C 07D 221:00 J, 7C 07D 209:00 J

17Q First examination report despatched

Effective date: 20011119

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI NL PT SE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040407

Ref country code: LI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040407

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040407

Ref country code: CH

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040407

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040407

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040407

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REF Corresponds to:

Ref document number: 69822937

Country of ref document: DE

Date of ref document: 20040513

Kind code of ref document: P

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040707

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040707

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040707

NLV1 Nl: lapsed or annulled due to failure to fulfill the requirements of art. 29p and 29m of the patents act
REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2217533

Country of ref document: ES

Kind code of ref document: T3

ET Fr: translation filed
PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IE

Payment date: 20050112

Year of fee payment: 8

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20050110

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20060113

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20040907

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20090203

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20090108

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20090107

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20090128

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20090113

Year of fee payment: 12

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20100113

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20100930

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100201

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100803

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100113

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20110309

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100113

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20110308

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100114